1. Field of the Invention
The present invention relates to a novel 5-pyrrolyl-6-halogeno-2-pyridylmethylsulfinylbenzimidazole derivative which is useful as an agent for prophylaxis and treatment of gastric and duodenal ulcers. More specifically, the present invention relates to a novel 5-pyrrolyl-6-halogeno-2-pyridylmethylsulfinylbenzimidazole derivative represented by the following general formula (I): ##STR2## and a pharmaceutically acceptable salt thereof, in which X represents S, SO or SO.sub.2,
Y represents halogen, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or alkyl, PA0 R.sub.3 represents hydrogen, C.sub.1 -C.sub.8 alkyl, --SR.sub.6, --N(R.sub.7)hd 2, 1-piperidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl, or a group of formula --OR.sub.6 or --O(CH.sub.2).sub.m --Z, wherein PA0 represents C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, optionally substituted C.sub.3 -C.sub.10 cycloalkyl, c.sub.2 -C.sub.5 fluoroalkyl, or phenyl or benzyl, each of which is independently substituted with one or more halogen or C.sub.1 -C.sub.4 alkyl or alkoxy optionally substituted with halogen, PA0 R.sub.7 represents hydrogen or C.sub.1 -C.sub.5 alkyl, PA0 Z represents a group of formula --O(CH.sub.2).sub.p --OR.sub.8, --O(CH.sub.2).sub.q --R.sub.9 or --O(CH.sub.2).sub.r O(CH.sub.2).sub.s --OR.sub.10, wherein PA0 m represents an integer of 2 to 10, and PA0 R.sub.4 and R.sub.5 independently from each other represent hydrogen or C.sub.1 -C.sub.5 alkyl, or when R.sub.4 and R.sub.5 together with the carbon atoms adjacent to pyridine ring form a ring, R.sub.4 and R.sub.3 or R.sub.3 and R.sub.5 represent --CH=CH--CH=CH--, --O(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n O--, --CH.sub.2 (CH.sub.2).sub.n -- or --OCH=CH--, wherein n denotes an integer of 1 to 4. PA0 Y represents halogen, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or alkyl, PA0 R.sub.3 represents hydrogen, C.sub.1 -C.sub.8 alkyl, --SR.sub.6, --N(R.sub.7).sub.2, 1-piperidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl, or a group of formula --OR.sub.6 or --O(CH.sub.2).sub.m --Z, wherein PA0 R.sub.6 represents C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, optionally substituted C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.5 fluoroalkyl, or phenyl or benzyl, each of which is independently substituted with one or more halogen or C.sub.1 -C.sub.4 alkyl or alkoxy optionally substituted with halogen, PA0 R.sub.7 represents hydrogen or C.sub.1 -C.sub.5 alkyl, PA0 Z represents a group of formula --O(CH.sub.2).sub.p --OR.sub.8, --O(CH.sub.2).sub.q --R.sub.9 or --O(CH.sub.2).sub.r O(CH.sub.2).sub.s --OR.sub.10, wherein PA0 m represents an integer of 2 to 10, and PA0 R.sub.4 and R.sub.5 independently from each other represent hydrogen or C.sub.1 -C.sub.5 alkyl, or when R.sub.4 and R.sub.5 together with the carbon atoms adjacent to pyridine ring form a ring, R.sub.4 and R.sub.3 or R.sub.3 and R.sub.5 represent --CH=CH--CH=CH--, --O(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n O--, --CH.sub.2 (CH.sub.2).sub.n -- or --OCH=CH--, wherein n denotes an integer of 1 to 4. PA0 Y represents halogen, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or alkyl, PA0 R.sub.3 represents hydrogen, C.sub.1 -C.sub.8 alkyl, --SR.sub.6 , --N(R.sub.7).sub.2, 1-piperidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl, or a group of formula --OR.sub.6 or --O(CH.sub.2).sub.m --Z, wherein PA0 R.sub.6 represents C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, optionally substituted C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.5 fluoroalkyl, or phenyl or benzyl, each of which is independently substituted with one or more halogen or C.sub.1 -C.sub.4 alkyl or alkoxy optionally substituted with halogen, PA0 R.sub.7 represents hydrogen or C.sub.1 .varies.C.sub.5 alkyl, PA0 Z represents a group of formula --O(CH.sub.2).sub.p --OR.sub.8, --O(CH.sub.2).sub.q --R.sub.9 or --O(CH.sub.2).sub.r O(CH.sub.2).sub.s --OR.sub.10, wherein PA0 m represents an integer of 2 to 10, and PA0 R.sub.4 and R.sub.5 independently from each other represent hydrogen or C.sub.1 -C.sub.5 alkyl, or when R.sub.4 and R.sub.5 together with the carbon atoms adjacent to pyridine ring form a ring, R.sub.4 and R.sub.3 or R.sub.3 and R.sub.5 represent --CH=CH--CH=CH--, --O(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n O--, --CH.sub.2 (CH.sub.2).sub.n -- or --OCH=CH--, wherein n denotes an integer of 1 to 4. PA0 X represents S, SO or SO.sub.2, PA0 Y represents halogen, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or methyl, PA0 R.sub.3 represents hydrogen, C.sub.1 -C.sub.8 alkyl, --SR.sub.6, --N(R.sub.7).sub.2, 1-piperidinyl, 4-morpholinyl, 4 -methylpiperazin-1-yl, 1-pyrrolidinyl, or a group of formula --OR.sub.6 or --O(CH.sub.2).sub.m --Z, wherein PA0 R.sub.6 represents C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 fluoroalkyl having 3 to 8 fluorine atoms, or phenyl which is substituted with one or more halogen or C.sub.1 -C.sub.4 alkyl or alkoxy optionally substituted with halogen, PA0 R.sub.7 represents hydrogen or C.sub.1 -C.sub.4 alkyl, PA0 Z represents a group of formula --O(CH.sub.2).sub.p --OR.sub.8, --O(CH.sub.2).sub.q --R.sub.9 or --O(CH.sub.2).sub.r O(CH.sub.2).sub.s --OR.sub.10, wherein PA0 m represents an integer of 2 to 10, and PA0 R.sub.4 and R.sub.5 independently from each other represent hydrogen or C.sub.1 -C.sub.5 alkyl, or when R.sub.4 and R.sub.5 together with the carbon atoms adjacent to pyridine ring form a ring, R.sub.4 and R.sub.3 or R.sub.3 and R.sub.5 represent --CH=CH--CH=CH--, --O(CH.sub.2).sub.n --, --CH.sub.2 (CH.sub.2).sub.n -- or --OCH=CH--, wherein n denotes an integer of 1 to 4 and the oxygen atom must be present in the R.sub.3 position. PA0 X represents S, SO or SO.sub.2, PA0 Y represents fluoro, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or methyl, PA0 R.sub.3 represents hydrogen, methyl, methoxy, ethoxy, ethoxyethoxy, 2,2,2-trifluoroethoxy or 3,3,3,2,2-pentafluoropropoxy, PA0 R.sub.4 represents hydrogen or methyl, and PA0 R.sub.5 represents hydrogen, methyl or ethyl. PA0 X represents SO, PA0 Y represents fluoro, PA0 R.sub.1 and R.sub.2 independently from each other represent hydrogen or methyl, PA0 R.sub.3 represents methoxy or ethoxy, and PA0 R.sub.4 and R.sub.5 independently from each other represent hydrogen, methyl or ethyl. PA0 L represents halogen, esterified hydroxy or acyloxy. PA0 Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are defined as in the compound of formula (I) above, PA0 t denotes 1 or 2, and PA0 M represents an alkali metal.
p and q independently from each other denote an integer of 1 to 3, PA1 r and s independently from each other denote an integer of 1 to 5, PA1 R.sub.8 represents hydrogen, lower alkyl, aryl or aralkyl, PA1 R.sub.9 represents hydrogen, alkoxycarbonyl, aryl or heteroaryl, and PA1 R.sub.10 represents hydrogen or lower alkyl, PA1 p and q independently from each other denote an integer of 1 to 3, PA1 r and s independently from each other denote an integer of 1 to 5, PA1 R.sub.8 represents hydrogen, lower alkyl, aryl or aralkyl, PA1 R.sub.9 represents hydrogen, alkoxycarbonyl, aryl or heteroaryl, and PA1 R.sub.10 represents hydrogen or lower alkyl, PA1 p and q independently from each other denote an integer of 1 to 3, PA1 r and s independently from each other denote an integer of 1 to 5, PA1 R.sub.8 represents hydrogen, lower alkyl, aryl or aralkyl, PA1 R.sub.9 represents hydrogen, alkoxycarbonyl, aryl or heteroaryl, and PA1 R.sub.10 represents hydrogen or lower alkyl, PA1 p and q independently from each other denote an integer of 1 to 3, PA1 r and s independently from each other denote an integer of 1 to 5, PA1 R.sub.8 represents hydrogen, lower alkyl, aryl or aralkyl, PA1 R.sub.9 represents hydrogen, alkoxycarbonyl, aryl or heteroaryl, and PA1 R.sub.10 represents hydrogen or lower alkyl,
The present invention also relates to a process for preparation of the compound of formula (I), as defined above, and a pharmaceutical composition for prophylaxis and treatment of gastric and duodenal ulcers which contains the compound of formula (I) as an active ingredient.
2. Background Art
Gastric and duodenal ulcers are a gastrointestinal disease caused by various factors such as mental stress, dietary habit, intake of irritable food, and the like, and occur mainly in lower esophagus, stomach or duodenum. In addition, when the gastric membrane is present in small intestine, the ulcers caused by gastric juice secreted therefrom may very rarely occur in small intestine. The cause of peptic ulcers can be generally classified into two cases, that is, one is the strengthening of an offence factor such as gastric acid or pepsin and the other is the weakening of a defense factor against such offence factor. Generally, it has been known that the main cause of duodenal ulcer is the strengthening of an offence factor and the gastric ulcer is mainly caused by the weakening of a defense factor, although the cause of gastric ulcers is somewhat varied depending on the attacked site.
Currently, therapeutic agents which have been commonly used for treatment of the peptic ulcers includes, for example, ant-acids for neutralizing gastric acid, anti-pepsin agents, agents for protecting the gastric mucous membrane, anti-cholinergic agents for inhibiting gastric secretion, para-sympatholytic agents, H.sub.2 -receptor antagonists, proton pump inhibitors, and the like. At the present time, since it has been disclosed that antacids and CNS-acting anti-ulcer agents provide only a unsatisfactory therapeutic effect and may cause adverse effects when they are administered for a long period, the use of H.sub.2 -receptor antagonists as agents for treating gastric and duodenal ulcers through a new acting mechanism has increased.
In addition, recently 5-methoxy-2-[[(4-methoxy-3,5-dimethyl -2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (Generic name: Omeprazole) having the following formula (A) has been developed and demonstrated as a good anti-ulcer agent having a superior effect over conventional H.sub.2 -receptor antagonists such as cimetidine, famotidine, ranitidine, nizatidine, roxatidine, and the like (see, U.S. patent specification Nos. 4,255,431, 4,337,257, 4,508,905 and 4,758,579, British Patent No. 2,134,523, European Patent Nos. 0,005,129 and 0,268,956) . In view of the acting mechanism, contrary to conventional H.sub.2 -receptor antagonists, Omeprazole is a specific proton pump inhibitor which blocks the proton pump of H.sup.+, K.sup.+ -ATPase present in the gastric mucous membrane to inhibit the gastric secretion at the final stage. In addition, Omeprazole has also an advantage of prolonged duration in comparison with conventional anti-ulcer agents. Accordingly, Omeprazole is widely used in various types of formulations. ##STR3##
Thus, the present inventors have extensively studied for a long time to develop novel anti-ulcer agents which have a benzimidazole structure similar to Omeprazole and exhibit a superior anti-ulcer effect over Omeprazole. As a result, we have synthesized a novel compound having the general formula (I), as defined above, and then identified that the compound of formula (I) has a superior anti-ulcer effect in comparison with Omeprazole. Thus, now we have completed the present invention.
Therefore, it is an object of the present invention to provide a novel 5-pyrrolyl-6-halogeno-2-pyridylmethylsulfinylbenzimidazole derivative having the general formula (I), as defined above, which is useful as an agent for prophylaxis and treatment of gastric and duodenal ulcers.
It is a further object of the present invention to provide a process for preparation of the novel 5-pyrrolyl-6-halogeno-2-pyridylmethylsulfinylbenzimidazole derivative of formula (I).
Further, it is another object of the present invention to provide a pharmaceutical composition for prophylaxis and treatment of gastric and duodenal ulcers, which contains the novel 5-pyrrolyl-6-halogeno-2-pyridylmethylsulfinylbenzimidazole derivative of formula (I) as an active ingredient.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Other many beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the summary of invention and the disclosure of invention describing the preferred embodiment, in addition to the scope of the invention defined by the claims.